The current version of CellDesigner requires Java2 Runtime Environment (JRE1.4.2 or later) on Windows (95 or later), MacOSX (10.3 or later), and Linux with X Window System. On MacOSX, Java 1.4.2_05 or later is required.
On Linux platform, running under twm and windowmaker window managers is recommended; some problems will arise if you use window environments other than these.
If SBW and its modules have already been installed, these modules are available. Especially time evolving simulation of editing models can be performed.

If you are interested in time evolving simulation and analysis on biochemical networks, we recommend you to install the Systems Biology Workbench (SBW) and SBW-powered software before you install CellDesigner.(*)Please check http://www.sbw-sbml.org/index.html and download the software from Software/Download section.
To install SBW and SBW-powered software, follow their installation instructions.

If you would like to use CellDesigner alone right now, you can postpone this step until you need simulation and/or analysis.

Note: SBW Linux version
As for CellDesigner Linux version, its installer can detect the SBW library which has been installed into the default path prompted by the SBW installer. The default path of SBW is the user home directory ($HOME/SBW/lib) . If you change the default path of SBW, make sure you set the right path when you install CellDesigner.

(*) Caution (Dec 2004)CellDesigner 2.0 was originally developed with SBW 1.0.5.
We are currently testing CellDesigner against newly released SBW 2.0, and preparing CellDesigner 2.1, which will be available soon.
In the meantime, follow the instruction for the setup "connecting SBW 2.0 and CellDesigner 2.0"

The current release is distributed in archived installer package for each operating system.

Windows: CDInstall_2_1_1_win.exe, Setup_SBW_1_modules.exe (*)

MacOSX: CDInstall_2_1_1_mac.zip

Linux: CDInstall_2_1_1_linux.bin

(*)
Setup_SBW_1_modules.exe is to setup the SBW modules that CellDesigner uses.

While J2RE is required for CellDesigner to run, the installers for Windows and Linux include it, and MacOSX has a Java runtime environment initially. Therefore, you do not need to download or install J2RE. (If you installed SBW, you have already had it anyway.) Download the one for your operating system and follow instructions below to install CellDesigner for each environment.

Windows:

Double click CDInstall_2_1_1_win.exe.
The installer window should open, and follow the message therein.

When completing the installation of CellDesigner, start SBW_1_modules.exe to install the SBW simulation modules.

Note: In case you have installed SBW 2.0 and you encounter an error while installing CellDesigner, there might be a possibility that the C++ Broker is up which prevents CellDesigner to start. Please try to kill the broker using the Task Manager, or restart your system before you resume the CellDesigner installation.

MacOSX:

Double click CDInstall_2_1_1_mac.zip.

The compressed installer should be recognized by Stuffit Expander and should automatically be expanded to CDIinstall_2_1_1. Then double click it.
The installer window should open, and follow the message therein.

Linux:

Open a shell and, cd to the directory where you downloaded the installer.

At the prompt type: sh ./CDInstall_2_1_1_linux.bin.
The installer window should open, and follow the message therein.

If you have installed SBW,

Select the install set according to your choice of SBW.

Set the path to the SBW library.

[Installed File Images]

After installation finished, you would see the following directories/files in the installation directory (CellDesigner2.1.1 by default).

Windows:

Double click shortcut icon CellDesigner2.1.1 in your desktop.
Or double click CellDesigner2.1.exe in the directory where you chose to install (C:\Program Files\CellDesigner2.1.1 by default).

MacOSX:

Click icon for CellDesigner in dock.
Or double click CellDesigner in the folder you chose to install (Application/CellDesigner2.1.1 in you home directory by default).

Linux:

On a shell, cd to the directory where you chose to create links and type ./runCellDesigner2.1.1.
Or type ./runCellDesigner2.1.1 after cd to the directory where you chose to install (CellDesigner in you home directory by default).

The Species represents, for example, proteins and other molecules in biochemical networks and genes in gene regulatory networks.

The Reaction represents, for example, biochemical reactions literally, interaction between proteins, and regulatory relations between genes.

The biochemical and genetic meanings of Species and Reactions are distinguished by their symbols. The list of all symbols that can be drawn using CellDesigner and their meanings are described in [Section 6 “Symbols and Expressions].

To change the symbols of Species / Reactions:

If you double click Species and Reactions., the dialog box will appear to alter its type.

Double click a Species (especially decorated one),
click and change anything in the dialog box, and then, see what is changed after click "Apply" button.

Double click a Species (especially decorated one),
click and change anything in the dialog box, and then, see what is changed after click "Reset" button.

If you want to create new Species, Reaction, or Compartment, use icons on the tool bar.

New Species:

Select an icon (placed in the tool bar) by click and then click a point on the canvas (draw area), where you want to place the new.

New Compartment:

Select an icon from the compartment bar (as shown below) by click and then drag a point to another on the canvas until the new becomes suitable size.

New Reaction:

Select an icon with an arrow on it, and then link Species to Species/Reaction on canvas.
(in details) Click Species on canvas you want to link by the Reaction in the order of start-point(s) to end-point(s). Reactions themselves are allowed to be endpoints of other Reactions.

You can add a note to any component (Species, Reaction, Compartment, and Protein).
The notes should be written in XHTML format. For details on XHTML tags and attributes, please check the XHTML 1.0 specification provided at http://www.w3.org/TR/xhtml1/

In this section, how to edit proteins with modification sites, such as "Cdc2" in the sample “M-Phase.xml”, is being described.

With CellDesigner, you can edit symbols of proteins with modification residues on a network diagram, and hence, describe detailed state transitions between Species of an identical protein with different modifications. The structure of modification residues, states, and state transitions of proteins are also stored in SBML Level 2 format with CellDesigner’s extended tags.

The model M-Phase.xml, you see, describes state transition of "Cdc2," where there are five "Cdc2"s. The five represent different Species, while essentially the same protein. Therefore, CellDesigner should handle data structure describing each protein in a model, so that several protein-type Species could have references to the same protein data. This data structure is called Protein.

You can see this Protein data by selecting the Protein tab in the List Area.
If you cannot see the Protein tab, click on the right arrow in the upper right corner of the List Area, and adjust the size of the List window appropriately.

Select "Cdc2" in the list and click Edit button.

The Protein dialog will appear. In this dialog, you can edit several properties of Protein, name, class, and residues (add, edit, and delete).

Changes in this dialog are reflected to all Species referring to this Protein.
The changes are also reflected to Heterodimers (complex of several Species) including such Species, as you expect.

The residues of proteins can be added in the Protein dialog, but the modification of the residue status (such as phosphorylated, etc.) is NOT maintained as Protein’s property, but as Species’ identity.

Therefore, modifications are edited by

Double-click Species in “select/move” mode.
In the dialog appeared, you can change the modification types. Note: You cannot add, edit, or delete modification residues in “Change Species Identity” dialog.

A Protein referred by the Species can be selected in the “Protein” pulldown in the dialog. If you want new protein, not listed in the “Protein” pulldown, select [New Protein] listed at the last and you can edit the new Protein here. Only in this case you can add, edit, and delete residues.

Block diagram gives a summary view of interactions with respect to a specific Species (especially Protein) and relation between its modification and activity as enzyme. Using this block diagram editor, complex relations between Proteins can be understood at a glance and the relation between modification states enzymic activity can easily be constructed.
Note: The editor is still prototype and user interface for editing is not fully functional.

Extract Regulation:

CellDesigner extracts the interactions where the Species regulates or is regulated by other Species, from process diagram, and displays its block diagram.

Open the dialog to check and edit Cdc2 Protein property (See. 3.1).

Click “edit block diagram” button and you can see the diagram as shown below.

At the top side of the rectangle placed in center, states of modification residues of Cdc2 and proteins that cause change of the states (phosphorylate or dephosphorylate) are shown. At the left and bottom sides, binding to CyclinB enzymic activity to Lamina are shown respectively.

For notation details of the block diagram, see Kitano (Biosilico1,No.5 (2003) pp.169—176) .

List in the dialog shows all the Species of Cdc2 and Complexes with other Species in process diagram (column) and their modification states and enzymic activity (row).

Modifications/Activations Relation:

You can edit logical relation between modification states and enzymic activity.

Select the symbol “&” and then place them on the diagram.

Select the arrow, then link “P”, “&”, ”□” and “■”.

[To delete a placed symbol, select the symbol and press × button in the toolbar.]

The arrows represent causal relationship and “&” , “|”, etc. are logical operators. Created logical relation can also be verified by checking consistency with contents of process diagram.

The above figures, the left is depicted by logical relation inferred by Species s29 only and the enzymic activity field of Species s28 is highlighted. The right is corrected by using the information of s28. (Note that the way of correction is not unique.)

When constructing a model using buttons on toolbars to create new Species, Reactions, and Compartments (in “create new“ mode), you cannot move any components unless click the select/move icon. In model building, creating new components and layout them are likely to be repeated successively. In such case, holding “s” key on your keyboard down makes the current edit mode to “select/move” temporally. After moving some components by drag, releasing the key makes the edit mode to “create new” immediately.

Note: If you want to create components one by one, select “Input Repeat” in Edit menu to OFF the checkmark.

In “select/move” mode, selected Species can be cut / copied to CellDesigner’s internal clipboard by [CTRL]-x / [CTRL]-c, and pasted to the edit canvas by [CTRL]-v. The copy-and-paste action makes “real” copies of the selected Species, which are SpeciesAliases in CellDesigner’s terminology, referring the original Species. Strictly speaking, all of the Species on edit canvas are SpeciesAliases referring each original Species. By this feature, CellDesigner has multiple copies of the same Species on an edit canvas (i.e. a model), to possess ability to make various expression of a network.

In “select/move” mode, by clicking multiple Species while holding the SHIFT key down, you can make a temporal group of the selecting Species. Moving, cutting, and copying them in a group are available. If you want the group to be permanent (saved to SBML), use [CTRL]-g while the temporary group is formed. This grouping feature is resembled to the situation, Species on a Compartment, while it has nothing to do with structure of the model. Therefore, if these two conflict each other in the canvas, “Species on a Compartment” structure has priority.

You can change the zoom of the display by clicking the following icons.

When you create a big model, it would be convenient to use the Bird’s Eye View to navigate inside the model. The Bird’s Eye View can be displayed by clicking the right most icon of the above tool bar. When you click the position you want to display in the Bird’s Eye View, you can move to the specified position.

As CellDesigner is compliant to SBML, all names of components in a model must be conforming to the SBML convention. CellDesigner 2.0 is now compliant to SBML Level 2 Version 1,1; any character that can be mapped to UTF-8 encoding can be used for the component names. If you want the special characters, such as + plus, line break, superscript and subscript, you should follow the special rules to input such characters.

Examples:::

A special character is expressed by a sequence of characters with precedent and follow up '_'s. Here are some examples:

Ca2+ ("Ca" with "2+" superscript)

Ca_super_2_plus__endsuper_

Ca_super_2+_endsuper_

G alpha beta gamma ("G" with Greek "αβγ" subscripts)

G_sub__alpha__beta__gamma__endsub_

G_sub_αβγ_endsub_

Complex of Cdc2 and CyclinB ("Cdc2" followed by "+CyclinB" in the new line).

Cdc2_br__plus_CyclinB

Cdc2_br_+CyclinB

For more details on displaying special characters, check “Name Expression” at Help menu.

Caution: CellDesigner uses the "name" attributes as information to distinguish Species. Therefore, even if the rendered names look the same, the different "name" attributes, for example, "Gα" and "G_alpha_", mean different Species.

CellDesigner can be used as a kind of SBML file editors for simulators. You can pass the SBML data from CellDesigner to the SBML compliant simulators via SBW. You can conduct simulation seamlessly from CellDesigner via SBW to evoke such SBML compliant simulators.

To conduct time evolving simulation, you also need to know some basics of the SBML specification. Here in this document, describes the minimum requirements for simulation.

Before you start simulation, you need to check if the SBW and SBW-powered simulator modules have been installed in the path mentioned in Section 1.2 “Install SBW and SBW Modules”.

To check if the SBW is properly installed, start CellDesigner and open a model. SBW menu in the main menu is enabled if your setup has correctly been done.

Check if there are any simulators listed in the SBW menu.
If you have installed the simulators of your choice correctly, they are listed under SBW menu. The following is the SBW menu in typical environment on Windows.

Typical SBW menu

Save Network Object Model Clipboard

Simulation Service

Save Model as Matlab ODE Function File

Save Model as Matlab SimuLink Function File

Gibson Simulator

"Simulation Service" appears if Jarnac has been installed. The others are default-installed.

From side of SBML model building, you should specify first at least some Species and its attributes, and Reaction and its attribute for simulation. The minimum requirement of their attributes might be:

Species Attributes

The attribute “initialAmount” should usually be changed to a positive value.
The attribute “formula” should be text string according to SBML Level 1 specification, probably including id (name in SBML Level 1) attribute of Species and parameters defined by the attribute “parameter.” These attributes can be set at the Species list shown in the List Area.

Reaction Attributes

The attributes and parameters of the Reaction can be specified at the Reaction dialog and their child dialogs.

Open and see simulation.xml in samples directory.

Check the Reactions list in the List Area to see how the kinetic laws and parameters are specified.

For the other parameters required, the default values specified in SBML Level 1 are used.

In this section, symbols for building models with CellDesigner are listed. Graphical notation and listing of the symbols are based on proposal by Kitano (http://www.sbw-sbml.org/workshops/sixth/sbmlsbwstockholm.htm). The symbol system for state-transition diagram and the residue state representation among the proposal are almost realized with CellDesigner.

6.1.1 Species

6.1.2 Modifications of Protein Residues

There are seven types of symbols for residue modification states. The residue symbols accompanied with their label (used for residue name and position in amino acid sequence) can be attached to all protein-type Species.

Phosphorylated

Acetylated

Ubiquitinated

Methylated

Hydroxylated

Empty

Don’t Care

Unknown

6.1.3 Compartment

There are ten types of Compartment symbols. For each type, the thick line indicates outside of its boundary.

(a) Available actions of UNDO and REDO are limited to actions making change on the draw canvas.

(b) Regarding Heteromultimer:
As CellDesigner adopts the alias structure (as described Section 4.2 “Cut, Copy and Paste”), any heteromultimer created out of SpeciesAliases is regarded as a new SpeciesAlias. Therefore, the attributes specified to the individual components (SpeciesAliases) will not be maintained in the newly created heteromultimer.
Once the heteromultimer is being created, you can no longer edit the individual components of the heteromultimer. To edit the individual component, you should release the heteromultimer, and edit them, then re-create them as a new heteromultimer.

(a) The problems are reported in printing / exporting images of the huge model due to the lack of the memory.

(b) When using CellDesigner in non-English environment on MacOSX and Linux, letters on dialog boxes from File menu are not correctly displayed.

For MacOSX, open “System Preferences” and click “International” icon from “Personal” row, and then click “Language” tab. In the window for choosing language, place “English” at the top. (Note: The terms quoted by “_“ depend on your environment.) Then start CellDesigner.